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June 2012
Age-related testosterone decline
Testing for syphilis
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CONTENTS
2
Age-related testosterone decline in males
Testosterone levels naturally decline with age in males. Some health
professionals claim that a clinical syndrome of testosterone deficiency, or
andropause, is being under diagnosed, which has led to dramatic increases in
testosterone prescribing and testing in many countries. Routine measurement
of testosterone levels is not indicated in older males. Testing should only be
considered in males who have clinically significant signs and symptoms of
late-onset hypogonadism.
10
Syphilis: testing for “the great imitator”
19
Appropriate use of the faecal occult blood test for
colorectal cancer
Over one hundred people per year in New Zealand are diagnosed with syphilis.
While this only represents a small number of patients, the incidence of syphilis
is increasing. Syphilis is most infectious in the earlier stages, therefore prompt
identification and treatment is required to prevent transmission. Recognising
the signs and risk factors and incorporating syphilis testing into sexual health
checks is essential.
Quiz feedback: CVD, diabetes and renal disease in elderly
people / Drug testing in adolescents (Best Tests; Mar, 2012)
Now online at www.bpac.org.nz
best tests | June 2012 | 1
Age-related
testosterone decline
in males
2 | June 2012 | best tests
The symptoms of male late-onset testosterone deficiency are non-specific and can be difficult to
distinguish from changes related to natural ageing. There is often uncertainty as to when the measurement
of testosterone is indicated. Testing should only be considered in males who have clinically significant
symptoms and signs of late-onset hypogonadism.
Testosterone and ageing
Testosterone production in males is regulated by
the hypothalamic-pituitary-gonadal (HPG) axis. The
hypothalamus secretes gonadotropin-releasing hormone
(GnRH) which causes the anterior pituitary to produce
luteinising hormone (LH) and follicle stimulating
hormone (FSH). LH then stimulates Leydig cells in the
testes to produce testosterone. The process is controlled
by a negative feedback loop, with testosterone inhibiting
the frequency and amplitude of hypothalamic and
anterior pituitary secretions. The majority of testosterone
is inactivated in the liver and excreted by the kidneys,
approximately 4% is converted to dihydrotestosterone via
a reductase enzyme and 0.2% to oestradiol via the enzyme
aromatase.1
Testosterone levels in males decline at the rate of
approximately 1% per year from age forty years.2
Interpretation of the clinical significance of this is
controversial. Some health professionals (predominantly
in North America) claim that a clinical syndrome, referred
to as “andropause”, is being under diagnosed. Conversely,
other health professionals describe this age-related
decline in testosterone as merely a barometer of natural
ageing. There is therefore no consensus on the prevalence
of clinically significant testosterone deficiency in the older
male population.
The two schools of thought have also resulted in
discrepancies in prescribing practice in different countries.
Between 1994 and 2003, testosterone prescription sales
in the United States increased by 1700%, while remaining
relatively constant in Europe.3, 4 Increases in the volume of
testosterone prescriptions have been recently reported
in Australia,5 however, this trend is not apparent in New
Zealand.
Significant increases in the volume of testosterone
prescribed means a similar increase in laboratory testing
of testosterone and other hormones. This article provides
guidance on when it is appropriate to investigate
suspected late-onset hypogonadism in males aged over
40 years.
Testosterone deficiency in older males
Testosterone deficiency that occurs in association with
advancing age is termed late-onset hypogonadism.
The symptoms of late-onset hypogonadism (Table 1,
over page) are often non-specific, with a weak overall
association with testosterone levels.8 A 2010 study of over
3000 males aged 40 to 79 years found that the combined
sexual symptoms of poor morning erection, low sexual
desire and erectile dysfunction (inability to achieve or
maintain penile erection sufficient for satisfactory sexual
performance) were useful in diagnosing testosterone
deficiency, in combination with laboratory testing of
testosterone levels.8
Primary and secondary hypogonadism
Late-onset hypogonadism can result from primary
or secondary causes, which can be due to congenital
abnormalities or acquired disease. In some cases, both
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“Andropause” and disease mongering
Recent articles in the Medical Journal of Australia
suggest that testosterone is being over prescribed
in Australia due to successful marketing by
pharmaceutical companies.6, 7
From 1992 – 2010 the volume of testosterone
prescribed per month in Australia increased by 1.5 to
4.3 times (depending on the State).5 It was concluded
that improved diagnosis of testosterone deficiency is
unlikely to account for the majority of this increase
and that it is more likely that it is being driven by the
use of testosterone for non-approved indications,
such as “andropause” and male sexual dysfunction.
primary and secondary causes are present, particularly in
people with long-term systemic diseases such as chronic
kidney disease, cirrhosis or chronic lung disease.
Primary hypogonadism is when there is decreased
testosterone production due to a testicular abnormality.
This may occur, for example, after infection or
chemotherapy and in a small percentage of males with
advancing age. Primary hypogonadism is characterised by
elevated LH due to the reduced negative feedback effect
of testosterone.
Secondary hypogonadism results from disorders of the
hypothalamic-pituitary axis, e.g. tumours, or congenital
or genetic conditions. Secondary hypogonadism is
characterised by low, or lower than expected, serum LH
levels in combination with low testosterone levels.
Measuring testosterone levels
Measurement of total serum testosterone (see panel
opposite) is generally sufficient to diagnose testosterone
deficiency. Assays which directly measure free
testosterone are not recommended due to poor reliability,
although free testosterone can be calculated through
additional testing in rare cases where unusually high or
Table 1: Signs and symptoms associated with testosterone deficiency in males9
More specific
Less specific
Decreased or absent early morning erection
Decreased energy, motivation and confidence (vitality)
Reduced libido
Depressed mood
Erectile dysfunction
Poor concentration and memory
Breast discomfort, gynaecomastia
Sleep disturbance and increased sleepiness
Loss of facial, axillary and pubic hair
Mild anaemia
Testicular atrophy
Reduced muscle bulk and strength
Infertility
Increased body fat
Height loss, low velocity fractures, low bone mineral
density
Decreased physical performance
Hot flushes, sweats
N.B. All of these signs and symptoms can be indicative of causes other than hypogonadism. Signs and symptoms should
be interpreted in the context of the entire clinical picture.
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low sex hormone-binding globulin (SHBG) levels may be
expected, e.g. patients with hyperthyroidism, cirrhosis or
taking anticonvulsants.10
Who should be considered for testing?
Testosterone testing should only be considered for males
who display symptoms and signs clinically suggestive
of hypogonadism. Routine testosterone testing in older
males is not recommended, as the results in the absence
of symptoms are unlikely to influence management.
Before considering investigating for late-onset hypogonadism, rule out factors that can cause a transitory
drop in testosterone levels and may explain the current
symptoms. This includes co-existing acute or chronic
illness, long-term use of medicines, e.g. opioids or
corticosteroids, high alcohol intake, illicit drug use, eating
disorders or excessive exercise.9
Free, bio-available and total testosterone
Only 1 – 2% of circulating testosterone is not bound
to protein. This fraction is termed free testosterone.11
Approximately 40 – 50% of circulating testosterone
is weakly bound to albumin.11 The free and albuminbound testosterone is referred to as bio-available.
The remaining testosterone in circulation is strongly
bound to SHBG. The amount of SHBG in circulation
therefore influences the amount of bio-available
testosterone. SHBG can be altered by factors such as
age, hepatic cirrhosis and hepatitis, hyperthyroidism,
obesity and the use of anticonvulsants.9 Total
testosterone refers to circulating, bio-available and
SHBG-bound testosterone.
Erectile dysfunction is common in males aged over
40 years and may be a reason for patients to request
a testosterone test.12 However, routine testing of
testosterone levels in males with erectile dysfunction
in the absence of other symptoms of late-onset
hypogonadism is not recommended.13 Although lateonset hypogonadism and erectile dysfunction both
become more common with age (and will often coexist), the two disorders have distinct pathophysiology
and erectile dysfunction is only rarely ever caused
by low testosterone levels.9 Erectile dysfunction is
most frequently caused by neurological or vascular
disease, some medicines (e.g. antidepressants or
antihypertensives) or psychosexual factors.13 Testosterone
treatment for erectile dysfunction is only effective (and
indicated) if the cause is a testosterone deficiency.9, 13
For further information see: “Selected topics in Men’s
Health” Best Tests (Sept, 2010) and “Erectile dysfunction”,
BPJ 12 (Apr, 2008).
Obesity in males is associated with decreased testosterone
levels.14 However, testing of testosterone levels in obese
males, who do not display symptoms of hypogonadism,
is not recommended, as treatment in the absence of
symptoms is unlikely to be of significant benefit. The
relationship between obesity and hypogonadism
is complex as low testosterone is both a cause and
consequence of obesity.15
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Investigating testosterone concentration
Blood samples should be taken in the early morning as
serum levels in males, particularly younger males, vary
throughout the day, e.g. highest at 8 am and lowest at 8
pm.16 The reference range for total serum testosterone
concentration in adult males differs between laboratories.
An approximate range is 8 – 35 nmol/L, however, if there
is doubt the reporting laboratory should be consulted.
Work is currently in progress internationally to standardise
testosterone assays and reference ranges.
Interpreting serum testosterone results
If a single early morning testosterone level is within the
reference range then no further testing is required.
Testosterone levels below the reference range should be
considered in the context of the patient’s symptoms. Low
testosterone levels require at least one repeat test, as 30%
of males with a mildly subnormal level will have a normal
level when the test is repeated.17 Acute illness or recent
alcohol intake can also affect testosterone levels.
The level of testosterone below which adverse health
outcomes emerge in older men is unknown.8 However, it
is generally agreed that clinically relevant symptoms and
a testosterone level below 8 nmol/L are required for a
diagnosis of late-onset hypogonadism.8
If a low testosterone level is detected, serum LH should
be measured, along with the confirmatory testosterone
test. Serum LH and FSH can be used to distinguish primary
from secondary hypogonadism. However, unless fertility
6 | June 2012 | best tests
is an issue, measurement of LH levels alone is sufficient.15
LH and testosterone levels can be interpreted as follows:
■ Primary hypogonadism is suggested by elevated
LH levels and a consistently low or borderline
testosterone level.
N.B. the testosterone reference range is population
based, therefore for some individuals the serum
testosterone may fall within the reference range, but
is low for them – as revealed by the high LH.
■ Secondary hypogonadism is suggested by low LH
or an inappropriately normal LH in the context of
consistently low testosterone levels
■ Low LH with a clearly normal testosterone
level suggests significant illness or exogenous
supplementation
Where secondary hypogonadism is suspected, a serum
prolactin test should be requested as prolactinoma is
a common type of pituitary tumour, which may be the
cause of secondary hypogonadism.
All patients with suspected hypogonadism should be
referred to an endocrinologist to confirm the diagnosis and
to discuss treatment options. In patients with suspected
secondary hypogonadism, assessment for anterior
pituitary dysfunction and MRI may be considered to
exclude the possibility of pituitary tumours.9 Testosterone
replacement should not be commenced until assessment
has taken place, as treatment is likely to suppress
endogenous production of testosterone and alter any
subsequent testosterone measurement.
Testosterone replacement for late-onset
hypogonadism in males
A three month trial of testosterone replacement may be
considered in patients with clinically significant symptoms
of hypogonadism and reproducible biochemical evidence
of a testosterone deficiency, following a detailed discussion
of the risks and benefits of treatment.9 It is recommended
that testosterone is initiated in consultation with an
endocrinologist. Testosterone replacement treatment for
hypogonadism is likely to be life-long if it provides benefit
to the patient (after the treatment trial).
Before testosterone treatment is commenced a clinical
history of prostate symptoms should be taken, a digital
rectal examination of the prostate conducted and PSA
and full blood count (to assess haematocrit) requested.
Testosterone replacement is generally not appropriate
for males who have: 9
Evidence of adverse effects associated
with testosterone replacement
A 2010 meta-analysis of studies of adult men with
low testosterone levels found that testosterone
treatment was associated with a three-fold increase
in the risk of polycythaemia and small, but significant
reductions in HDL cholesterol.19 However, the same
analysis did not find significant effects on all-cause
mortality, prostatic or urological outcomes or
cardiovascular events. In contrast, the Testosterone in
Older Men with Mobility Limitations (TOM) trial found
significantly increased cardiovascular-related adverse
effects in 23 of 106 men receiving testosterone
treatment, compared to six of 103 receiving placebo.
This resulted in the trial being halted early. However,
this study has been criticised for its small sample size
and the potentially elevated cardiovascular risk of
participants at baseline.
■ Diagnosed prostate or breast cancer
■ Palpable prostate nodule or induration, or PSA
> 4 ug/L (> 3 ug/L in males with an elevated risk
of prostate cancer, e.g. first-degree relative with
prostate cancer)
■ Severe lower urinary tract symptoms associated with
benign prostatic hypertrophy
■ An elevated haematocrit (> 50%)
■ Untreated severe sleep apnoea
■ Poorly controlled heart failure
There is no convincing evidence that testosterone
treatment is causally associated with the development
of new prostate cancer, however, occult prostate cancer
should be actively excluded before treatment begins.
Testosterone should not be prescribed to males who wish
to conceive or to treat male infertility. Testosterone within
the testes is required for spermatogenesis, however,
exogenous testosterone will decrease sperm production
through the negative feedback effect of testosterone on
gonadotropins.9
Testosterone replacement treatment is not indicated for
males with testosterone levels which are intermittently
low, or with low levels caused by medicines or lifestyle
factors (e.g. drug or alcohol misuse, excessive exercise).9
best tests | June 2012 | 7
The most significant adverse effects associated with
testosterone treatment are prostatic hypertrophy and
polycythaemia, which may occur within three months of
treatment initiation.9, 18 Mild hyperbilirubinaemia has also
been reported.
Prescribing testosterone
In New Zealand, testosterone is available in the following
forms:
■ Orally as testosterone undecanoate, e.g. initially
120 – 160 mg daily for two to three weeks, followed
by a maintenance dose of 40 – 120 mg daily.20 This
preparation is poorly absorbed and should be taken
in divided doses with food. Depending on baseline
testosterone levels, treatment may be started at a
lower dose to reduce the risk of adverse effects.
■ Testosterone patches, e.g. two 2.5 mg/day patches
applied before bed.21 This often causes local skin
irritation and can be poorly tolerated.
■ Injectable (intramuscular) – either long-acting
testosterone cypionate or testosterone esters, e.g. 50
– 400 mg testosterone cypionate every two to four
weeks.22 Reandron is a very long-acting injectable
form of testosterone undecanoate, which has the
advantage of 10 – 12 weekly administration, but is
not subsidised.
Prescriptions for oral and injectable testosterone
require consultation with and recommendation from an
endocrinologist (or other relevant specialist) in order to
be subsidised. Testosterone patches are fully-subsidised,
without restriction. However, it is recommended that any
testosterone preparations are prescribed in consultation
with an endocrinologist.
Follow-up is recommended after three months in order
to assess the effect of treatment, ask about adverse effects
and alter the dose if necessary.
Testosterone replacement treatment, particularly
injections, can be associated with a placebo effect,
therefore a second follow-up three months later is
recommended to ensure that any benefits of treatment
are sustained.
Within the first three to six months of treatment, a PSA
test and a digital prostate examination should occur. This
should be repeated annually if treatment continues.15 If
the PSA is significantly elevated then discussion with an
urologist is recommended.
The role of testosterone measurement in patients on
testosterone treatment is not clear. Routine monitoring
of testosterone levels is not required. However, in patients
using injectable preparations, it may be useful to determine
their trough level immediately prior to administering
their next dose. The target testosterone concentration is
in the mid-normal range. For example a concentration of
14 to 24 nmol/L is recommended for patients receiving
testosterone cypionate injections.9
Androgen misuse
Unexpected testosterone, LH, FSH and SHBG levels
can result from illicit use of androgens (“anabolic
steroids”). Classic symptoms include truncal acne,
excessive muscularity, testicular atrophy and
gynaecomastia, usually in association with obsessive
and intense exercise regimens. Consider asking
specific questions regarding androgen misuse to
males who display these behaviours and signs.
8 | June 2012 | best tests
Males who are currently using androgens may have
elevated testosterone and suppressed LH, FSH
and SHBG. Suppression of testosterone as well as
LH, FSH and SHBG can indicate a recent history of
androgen misuse.4 The rate of recovery from HPG
axis suppression is dependent on the duration and
severity of the misuse, but will generally occur within
12 months after cessation of androgens.4
ACKNOWLEDGEMENT: Thank you to Dr Cam
Kyle, Clinical Director of Biochemistry and
Immunology, Diagnostic Medlab, Auckland and
Associate Professor Geoff Braatvedt, Physician
and Endocrinologist, Department of Medicine,
University of Auckland for expert guidance in
developing this article
References
1. Allan CA, McLachlan RI. Testosterone deficiency in
men. Diagnosis and management. Aust Fam Physician
2003;32(6):422–7.
12. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence
and its medical and psychosocial correlates: results of the
Massachusetts Male Aging Study. J Urol 1994;151(1):54–61.
2. Feldman HA, Longcope C, Derby CA, et al. Age trends
in the level of serum testosterone and other hormones
in middle-aged men: longitudinal results from the
Massachusetts male aging study. J Clin Endocrinol Metab
2002;87(2):589–98.
13. Jack G, Zeitlin SI. The role of routine serum testosterone
testing: routine hormone analysis is not indicated as
an initial screening test in the evaluation of erectile
dysfunction. Rev Urol 2004;6(4):203–6.
3. Bhasin S, Singh AB, Mac RP, et al. Managing the risks of
prostate disease during testosterone replacement therapy
in older men: recommendations for a standardized
monitoring plan. J Androl 2003;24(3):299–311.
4. Handelsman DJ. Androgen misuse and abuse. Best Pract Res
Clin Endocrinol Metab 2011;25(2):377–89.
5. Handelsman DJ. Pharmacoepidemiology of testosterone
prescribing in Australia, 1992-2010. Med J Aust
2012;196(10):642–5.
6. Katelaris A. Testosterone up. A case of disease mongering?
Med J Aust 2012;196(10):611.
7. Vitry AI, Mintzes B. Disease mongering and low testosterone
in men: the tale of two regulatory failures. Med J Aust
2012;196(10):619–21.
8. Wu FCW, Tajar A, Beynon JM, et al. Identification of lateonset hypogonadism in middle-aged and elderly men. N
Engl J Med 2010;363(2):123–35.
9. The Endocrine Society. Testosterone therapy in adult
men with androgen deficiency syndromes: An Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab
2010;95(6):2536–59.
14. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of
hypogonadism in males aged at least 45 years: the HIM
study. Int J Clin Pract 2006;60(7):762–9.
15. Dandona P, Rosenberg MT. A practical guide to male
hypogonadism in the primary care setting. Int J Clin Pract
2010;64(6):682–96.
16. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian
rhythmicity in blood testosterone levels with aging in
normal men. J Clin Endocrinol Metab 1983;56(6):1278–81.
17. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay J.
Intraindividual variation in levels of serum testosterone
and other reproductive and adrenal hormones in men. Clin
Endocrinol (Oxf ) 2007;67(6):853–62.
18. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone
replacement in hypogonadal men. J Clin Endocrinol Metab
2000;85(8):2670–7.
19. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical
review 1: Adverse effects of testosterone therapy in
adult men: a systematic review and meta-analysis. J Clin
Endocrinol Metab 2010;95(6):2560–75.
20. Arrow Pharmaceuticals Limited. Testosterone - Medicine
data sheet. 2010. Available from: www.medsafe.govt.nz
(Accessed Jun, 2012).
10. Editor: Kyle C. A handbook for the interpretation of
laboratory tests. 4th ed. Diagnostic Medlab; 2008.
21. Hospira NZ Limited. Androderm. 2009. Available from: www.
medsafe.govt.nz (Accessed Jun, 2012).
11. Kaufman JM, Vermeulen A. The decline of androgen levels
in elderly men and its clinical and therapeutic implications.
Endocr Rev 2005;26(6):833–76.
22. Pfizer New Zealand Ltd. Depo Testosterone: Testosterone
cypinoate injection. 2011. Available from: www.medsafe.
govt.nz (Accessed Jun, 2012).
best tests | June 2012 | 9
Syphilis:
testing for “the great imitator”
10 | June 2012 | best tests
The incidence of syphilis in New Zealand has increased dramatically over the last decade. As syphilis is
highly infectious in the early stages, prompt identification is important. However, the perceived rarity of
syphilis, combined with often non-specific symptoms, mean this can be difficult. Recognising the signs
and risk factors and incorporating syphilis testing into sexual health checks, is essential for controlling the
growing number of new syphilis infections.
A recent increase in new syphilis infections
Syphilis is a sexually transmitted infection caused by the
spirochete (spiral shaped) bacterium Treponema pallidum.
It is unknown where and when syphilis first emerged, but
one theory is that explorers carried syphilis from the “New
World” back to Europe with them in the 1400s, where it
spread so quickly it became known as the Great Pox. Many
famous historical figures are thought to have had syphilis,
including Vincent van Gogh, Adolf Hitler and Leo Tolstoy,
and prostitutes infected with syphilis are most likely the
origin of the “femme fatale” character in literature. It was
not until the discovery of penicillin in the 1940s that the
prevalence of syphilis began to decline.1
In New Zealand, less than 20 cases of syphilis were being
reported each year by the early 2000’s.2 However, the
incidence of syphilis is now beginning to increase again,
with the most recent data showing that 119 cases were
reported by sexual health clinics in New Zealand in
2010.3, 4 While in absolute terms these numbers are low,
they represent a 600% increase in prevalence in less than a
decade. Similar increases have been occurring worldwide
and have been attributed to factors such as decreases in
the resources allocated to the diagnosis and control of
syphilis, increased international travel and increases in the
number of men who have sex with men.1
Although syphilis is still a relatively rare condition, it should
be considered as part of a sexual health check. Syphilis in
New Zealand is most commonly seen in men who have sex
with men (in particular, HIV positive men), in heterosexual
people who have sex while overseas, particularly in South
East Asia and Africa and in immigrants, particularly those
from the Asia-Pacific region.
best tests | June 2012 | 11
The symptoms of syphilis
Syphilis is termed the “great imitator”, as symptoms are
often non-specific or mimic other infectious or immune
mediated conditions, e.g, the rash seen in secondary
syphilis may resemble pityriasis rosea. Approximately 50%
of people with syphilis are asymptomatic.
The progression of syphilis is divided into three stages;
primary, secondary and tertiary. An asymptomatic latent
period, which may last more than a decade, separates the
secondary and tertiary stages. The time between infection
and development of initial symptoms is on average 21
days, but ranges from 10 – 90 days.5 People with syphilis
are highly infectious during the primary and secondary
stages, with infectivity declining in the latent and tertiary
stages. Syphilis spirochetes are able to pass through
intact mucous membranes and compromised skin, so are
transmissible via kissing and vaginal, oral and anal sex.1
Consistent condom use reduces, but does not eliminate,
the risk of syphilis infection.6 It is estimated that the rate of
transmission between people with primary or secondary
syphilis and their sexual partners is 30%.1
Primary syphilis
multiple lesions may be present (Figure 1).7 The chancre is
firm, painless and can vary in size up to approximately 3 cm.
It generally appears at the site of disease transmission, and
therefore may not be noticed by the patient if it is inside the
vagina, anus or oral cavity. Non-tender lymphadenopathy
may develop near the site of the chancre.
The chancre typically resolves within four to eight weeks
and does not require localised treatment, although
antibiotic treatment to prevent syphilis infection from
progressing is necessary (Page 16).7
Secondary syphilis
Secondary syphilis develops three weeks to three months
after the appearance of primary syphilis, if left untreated.7
Secondary syphilis is characterised by skin rashes
and mucous membrane lesions. The typical rash is a
widespread, symmetrical eruption of slightly scaly, reddish
brown plaques (Figure 2) that also occurs on the palms of
the hands and the soles of the feet (Figures 3). However,
rashes may be non-specific, appear on other parts of the
body or resemble rashes caused by other conditions, such
as pityriasis rosea. Rashes may be so faint that they are not
noticed.
The initial stage of syphilis is typically marked by the
appearance of a single chancre (ulcer-like lesion), although
Condylomata lata may also be present. These are moist,
grey, pink or white, raised, wart-like lesions or plaques
Figure 1: Penile chancre in primary syphilis (Supplied by
Figure 2: Disseminated rash in secondary syphilis Pox
Dermnet NZ)
(Supplied by Dermnet NZ /Dr John Adams)
12 | June 2012 | best tests
which are highly infectious areas of concentrated
spirochete particulates. They can occur on the penis
(Figure 4), vulva, rectum, mouth, throat, larynx, inner
thighs, armpits and under breasts.7
Other symptoms of secondary syphilis are non-specific
and include flu-like symptoms, such as lymphadenopathy,
tiredness, headache, sore throat, fever and weight loss.7, 8
The rashes and lesions associated with secondary syphilis
typically resolve within two to six weeks. Antibiotic
treatment reduces the duration of symptoms and prevents
progression to tertiary disease.8
Tertiary syphilis
Approximately one-third of untreated people will develop
tertiary syphilis. This stage occurs after a latent period,
when infection is identifiable on serological testing but
the patient does not have symptoms or signs. The tertiary
stage usually appears within three to ten years after
syphilis was first acquired, although it can appear up to 40
years later.1
Figure 3: Characteristic rash on the foot in secondary
syphilis. (Supplied by Dr Edward Coughlan)
Signs, symptoms and long term sequelae of tertiary
syphilis include:1,7
■ Neurological infection (neurosyphilis): numbness
in arms, legs and face, paralysis, gradual blindness,
changes in mental state and eventually dementia
■ Cardiovascular disease: classically chronic
inflammation of the aorta resulting in aneurysm
formation, aortic valve incompetence and, in the
longer term, congestive heart failure
Figure 4: Condylomata lata in secondary syphilis
(Supplied by Dermnet NZ/Dr John Adams)
■ Granulomatous lesions (gummas): painless rubbery
nodules mostly seen on the skin, mouth and throat
that may ulcerate, or form as lesions in the long
bones, which typically cause bone pain at night
The Oslo study estimated the probability of dying as a
result of untreated syphilis to be 17% in males and 8% in
females after 40 years infection.9 The infamous Tuskagee
study, which exploited a vulnerable patient population
and withheld treatment after it became available, found
that after 20 years of follow up, cardiovascular disease or
neurosyphilis was the primary cause of death in 30% of
African American males with syphilis.10
best tests | June 2012 | 13
Determining the risk of exposure to syphilis
Yaws in the Asia Pacific region
Treponemal bacteria are responsible for a number
of diseases other than syphilis, such as yaws, bejel
and pinta. All have similar symptoms and outcomes
to syphilis, but are not sexually transmitted.12 These
diseases are endemic to many tropical regions, but
World Health Organisation eradication efforts have
led to a greatly reduced number of people with new
infections.12
Yaws is likely to be the most common non-syphilitic
treponemal infection to be seen in immigrants to
New Zealand, particularly those from the Pacific and
Asia. While the likelihood of seeing a patient with
yaws is very low, many may have been exposed to this
infection during childhood. The antibodies produced
by the immune system in response to yaws remain
present for life.12 As such, people with a previous
yaws infection will always return a reactive result on
specific serology testing (Page 15). This should be
taken into consideration if investigating for syphilis
in a patient who has immigrated from a country or
region with an increased prevalence of any tropical
treponemal disease.
As part of a sexual health check, ask about behaviours or
factors that may increase a person’s risk of exposure to
syphilis.
People with an increased risk of syphilis include those
who:
■ Originate from a country where syphilis is common,
e.g. Sub-Saharan Africa, Asia-Pacific (especially Fiji),
South America or Eastern Europe
■ Have had sex with a person from a county where
syphilis is prevalent
■ Are male and have had sex with other males
■ Are HIV positive or have had sex with someone who
is HIV positive
■ Have multiple sexual partners
■ Have had sexual contact with a person diagnosed
with syphilis
Patients at increased risk should be examined for signs
and symptoms of syphilis. Syphilis serology (opposite)
should be requested, along with other STI investigations,
including HIV.7 Ulcer-forming genital diseases, such as
syphilis, increase the likelihood of transmission of HIV and
other STIs by five to ten times.5, 11
Specific signs which indicate an increased likelihood of
syphilis include:
■ Chancre (microscopy required, Page 16)
■ Condyloma lata
■ Rash on the palms of hands and on the soles of feet
(strongly suggestive of secondary syphilis)
■ Rash on the torso or lymphadenopathy not
attributable to another condition
Laboratory testing for suspected syphilis
Syphilis serology should be requested in patients at
increased risk or with clinical features suggestive of syphilis.
Patients with a suspected chancre should also be referred
to a sexual health clinic or laboratory for assessment and
microbiological examination of the lesion.
N.B. Syphilis serology is also included in the first antenatal
14 | June 2012 | best tests
screen in women who are pregnant and is required as part
of an immigration medical examination.
Serological testing
There are two types of syphilis serology test – non-specific
(non-treponemal) serology and specific (treponemal)
serology. Non-specific tests detect antibodies that bind
to antigens that are, or are similar to, those expressed
by Treponema pallidum or expressed on host tissues
during infection. These tests, such as the Rapid Plasma
Reagin (RPR) and Venereal Disease Research Laboratory
(VDRL) test, were traditionally used as screening tests for
syphilis, and to measure disease activity and response to
treatment.13 They are inexpensive to perform (compared
to specific tests) but have a high false-positive rate,
particularly in women who are pregnant, in people with
cancers, autoimmune disorders, co-morbid viral infections,
in older people and in people who use illicit drugs.7, 14
Antenatal screening and congenital
syphilis
Congenital syphilis occurs when infection is passed
vertically from mother to infant in-utero. The risk
of transfer in-utero is approximately 75 – 95% in a
mother with primary syphilis. The risk of a mother
passing infection to a foetus remains for up to seven
years post infection, if untreated.8 The mother does
not need to be symptomatic to pass on the infection.
Serology testing for syphilis is included in the first
antenatal screen. Testing should be repeated at 28
weeks and prior to delivery in women with a high risk
of syphilis infection, such as recent immigrants from
high-risk countries.5
Specific tests detect antibodies that bind to proteins
derived from Treponema pallidum. These tests, such as
the Treponemal pallidum Particle Agglutination (TTPA),
Treponema pallidum Haemagglutination (TPHA) and
Fluorescent Treponemal Antibody (FTA) test, have
commonly been used to confirm the diagnosis of syphilis.13
They are more expensive than non-specific tests, but
have a low false-positive rate. More recently, the Enzyme
immunoassay (EIA) and derivative immunoassays, such as
the Chemiluminescent Microparticle Immunoassay (CMIA),
that use specific Treponema pallidum antigens, have been
developed. These tests are less expensive and have altered
the way serology is used for testing for syphilis.
The approach generally used by laboratories in New
Zealand is to perform an initial test with EIA. If this is
positive, the diagnosis is confirmed using TPPA. Disease
activity is then determined using RPR.14, 15 Depending
on the patient-management system in use and the
methodology of the local laboratory, clinicians either
select “syphilis serology” on the laboratory request form or
request the individual tests.
Interpreting syphilis serology
Syphilis serology results should be interpreted within the
overall clinical picture, i.e. clinical examination, patient
history and risk profile. Table 1 (over page) may be useful
in aiding interpretation.
best tests | June 2012 | 15
EIA, TPPA and RPR results are expressed as “reactive” or
“non-reactive”. RPR results also include a titre, with higher
titres indicating greater disease activity. N.B. People who
have had a past treponemal infection, including nonvenereal infections such as yaws, will remain reactive on
specific treponemal tests for their lifetime.7, 14
Discussion with a sexual health or infectious disease
physician is recommended if results are contradictory or
difficult to interpret.
(DFA) stains for microscopy can be used,16 however, the
availability of this method is variable.
Topical treatment should not be applied to the chancre
and systemic antibiotics should not be prescribed until
the sample has been taken as this may alter the results.16
Syphilis serology should also be requested.
Management of syphilis: refer for treatment
Patients who have tested positive for syphilis should be
referred urgently to a sexual health or infectious disease
physician for treatment.14
Referral for microscopy is required for patients with a
chancre
If a patient presents with a suspected chancre, they
should be referred to a sexual health clinic or laboratory
for assessment and examination of the exudate from the
lesion. Dark field microscopy is used to detect bacterium
particulates (spirochetes).7
Exudate from oral and anal chancres cannot be reliably
examined with standard dark-field microscopy due to the
likelihood of contamination. Direct fluorescent antibody
Benzathine benzylpenicillin* injection is the first-line
treatment for syphilis at all stages. Tetracyclines, some
macrolides and cephalosporins can be used as an
alternative if the patient is allergic to penicillin. Penicillin
is the only recommended treatment in women who are
pregnant. Skin testing for penicillin allergy followed by desensitisation is recommended for pregnant women with a
history of penicillin allergy.7
Table 1: Interpreting syphilis serology
EIA
TPPA
RPR
Interpretation
Non-Reactive
Not tested
Not tested
No evidence of syphilis, or too early, retest
in one month if strong suspicion based on
clinical evidence
Reactive
Non-Reactive
Non-Reactive
Possible early primary, latent or false-positive,
retest in one month
Reactive
Non-Reactive
Reactive
Probable early primary, false positive possible
but unlikely, retest in two weeks
Reactive
Reactive
Non-Reactive
Evidence of past infection or possible latent
infection, history will help to differentiate
Reactive
Reactive
Reactive
Current syphilis
* Originally published as Penicillin G
16 | June 2012 | best tests
Effective treatment usually results in a decline in RPR titres,
although a return to pre-infection levels may take many
years.
Follow-up and partner notification
Sexual partner notification is necessary for all people
diagnosed with syphilis. This is usually carried out by the
sexual health clinic.
If the patient has primary syphilis, all sexual partners
within the last three months should be contacted, offered
testing and begun on empiric treatment, regardless of
serology results.14
If the patient has secondary syphilis, all sexual partners
within the last six months should be contacted and offered
testing. Empiric treatment should be commenced if sexual
contact has been within the last three months, regardless
of serology results.
If the patient has early-latent syphilis or syphilis of
unknown duration with an RPR titre of 1:32 or more, all
sexual partners within the last 12 months should be
contacted and offered testing. Empirical treatment should
be commenced if sexual contact has been within the last
three months regardless of serology results.14
In most cases, patients with late-latent or tertiary syphilis
are unable to transmit syphilis infection. Current partners
and children of women with late-latent or tertiary syphilis
should be tested.
Syphilis is not a Notifiable Disease, but surveillance of cases
is performed by Environmental Science and Research Ltd
(ESR) through voluntary reporting by laboratories and
sexual health clinics.
ACKNOWLEDGEMENT: Thank you to Dr Edward
Coughlan, Clinical Director, Christchurch Sexual
Health, Canterbury DHB, Associate Professor
Mark Thomas, Infectious Diseases Specialist,
Department of Molecular Medicine and Pathology,
University of Auckland, Dr Sunita Azariah Sexual
Health Physician, Auckland Sexual Health Service
and Dr John Bannister, Registrar, Auckland Sexual
Health Service, for expert guidance in developing
this article.
best tests | June 2012 | 17
References
1. Walker G. Antibiotics for syphilis diagnosed
during pregnancy. Cochrane Database of Syst Rev
2010;(3):CD001143.
2. The Environmental Institute of Science and Research (ESR).
Sexually transmitted infections in New Zealand: 2001.
Ministry of Health; 2002. Available from: www.surv.esr.cri.nz
(Accessed Jun, 2012).
3. The Environmental Institute of Science and Research (ESR).
Sexually transmitted infections in New Zealand: 2003.
Ministry of Health; 2004. Available from: www.surv.esr.cri.nz
(Accessed Jun, 2012).
4. The Environmental Institute of Science and Research (ESR).
Sexually transmitted infections in New Zealand: 2010.
Ministry of Health; 2011. Available from: www.surv.esr.cri.nz
(Accessed Jun, 2012).
5. Kollmann TR, Dobson S. Chapter 16 - Syphilis. Infectious
Diseases of the Fetus and Newborn (7th Ed). Philadelphia:
W.B. Saunders; 2011. p.524–63.
6. Koss C, Dunne E, Warner L. A systematic review of
epidemiologic studies assessing condom use and risk of
syphilis. Sex Transm Dis 2009;36(7):401–5.
7. Ngan V. Syphilis. DermNet NZ. 2011. Available from: www.
dermnetnz.org/bacterial/syphilis (Accessed Jun, 2012).
9. Clark EG, Danbolt N. The Oslo study of the natural history of
untreated syphilis: An epidemiologic investigation based
on a restudy of the Boeck-Bruusgaard material a review and
appraisal. J Chronic Dis. 1955;2(3):311–44.
10. Olansky S. Untreated syphilis in the male Negro: Twenty
years of clincial observation of untreated syphilitic
and presumably non-syphilitics groups. J Chronic Dis.
4(177):1956.
11. Karp G, Schlaeffer F, Jotkowitz A, Riesenberg K. Syphilis and
HIV co-infection. Euro J Int Med 2009;20(1):9–13.
12. Lal S, Dhariwal AC. Yaws, Pinta, and Endemic Syphilis. Int
Encyclo Pub Health. Oxford: Academic Press; 2008. p. 651–7.
13. Hoover K, Radolf J. Serodiagnosis of syphilis in the
recombinant era: Reversal of fortune. J Infect Dis
2011;204(9):1295–6.
14. The New Zealand Sexual Health Society (NZSHS). Syphilis.
NZSHS: Auckland; 2009. Available from: www.nzshs.org/
treatment_guidelines/Syphilis_2009.pdf (Accessed Jun,
2012).
15. Editor: Kyle C. A handbook for the interpretation of
laboratory tests. 4th ed. Diagnostic Medlab; 2008.
16. Brown D, Frank J. Diagnosis and management of syphilis.
Am Fam Physician 2003;68(2):283–90.
8. Longo D, Fauci A, Kasper D, et al. Harrison’s principles of
internal medicine. 18th ed. New York: Mc Graw Hill Medical;
2012. p. 1384-8.
QUIZ FEEDBACK
Best Tests
March 2012
This quiz feedback provides an
opportunity to revisit Best Tests, March
2012, which focused on CVD, diabetes
and renal disease in elderly people / Drug
testing in adolescents.
This is now available from our website:
www.bpac.org.nz
Appropriate use of
the faecal occult
blood test
for colorectal cancer
What is a faecal occult blood test?
A faecal occult blood test (FOBT) detects the presence of
haemoglobin in the faeces, which may indicate colorectal
adenomas or cancers.
There are two types of FOBT; gFOBT which involves the
use of a guaiac impregnated card and iFOBT in which
haemoglobin is detected immunologically. The relative
sensitivity of these tests is influenced by the amount of
haemoglobin present in the faeces.
In New Zealand, laboratories use either gFOBT, iFOBT or
gFOBT in conjunction with iFOBT as a confirmatory test.
Laboratories using gFOBT alone may require the patient
to undertake dietary restrictions two days prior to testing.
This should be discussed with individual laboratories. It is
not necessary to specify the type of test when requesting
a FOBT.
Are faecal occult blood tests effective?
There is evidence that FOBT is an effective method for
screening for colorectal cancer. A 2007 Cochrane metaanalysis found that iFOBT or gFOBT screening in people
aged 45 to 75 years prevents approximately one in six
deaths due to colorectal cancer.1 However, approximately
80% of positive FOBT results are false-positives as there
are many other causes for gastrointestinal bleeding, such
as haemorrhoids or anal fissures. This can lead to anxiety
and potentially unnecessary invasive procedures, e.g.
colonoscopy.1
When should a faecal occult blood test be
requested?
There is currently no national FOBT screening programme
for colorectal cancer in New Zealand, however, a four
year pilot in the Waitemata District Health Board region
best tests | June 2012 | 19
is underway. This will determine if a national screening
programme is appropriate for New Zealand.
Routine use of FOBT is not recommended, until such a time
that a screening programme is established. The decision to
request a FOBT should be made on an individual basis in
patients aged over 50 years, whose risk does not indicate
referral for colonoscopy, based on colorectal cancer
management guidelines.2
When is a faecal occult blood test not appropriate?
A FOBT is not recommended as a surveillance tool for
people at increased risk of colorectal cancer or for people
with a previous history of colorectal cancer, or as an
investigation tool for people with symptoms of colorectal
cancer. Symptomatic people should be referred on the
basis of risk, symptoms and clinical examination. People at
increased risk of colorectal cancer, or who have a previous
history of colorectal cancer require regular colonoscopy.2
Local resourcing of colonoscopy services may influence
the pathway of evaluation. This should be discussed with
local DHBs.
The use of FOBT in people aged under 50 years is not
recommended. The proportion of false-positive results
increases significantly in this age group, because the
background rates of colorectal cancer are lower.
In people aged over 50 years, factors such as advanced
age, co-morbidities, reduced life expectancy or reduced
fitness for invasive procedures should be considered
before requesting a FOBT.
For further information see: “Surveillance of people at
increased risk of colorectal cancer”, BPJ 44 (May, 2012).
How is the sample collected?
Faecal sample collection methods vary depending on the
laboratory and whether or not a purpose-made collection
kit is used. Check with your local laboratory.
Generally, a sample from two or three bowel movements
is collected by the patient with a spatula, brush or cloth
which is then stored in separate specimen containers, or
applied to the cardboard patches of a kit. The sample
should then be delivered to the laboratory as soon
as practically possible.
20 | June 2012 | best tests
How should the results of a faecal occult blood
test be managed?
N E W C L I N I C A L AU D I T
A positive result
A patient with a positive FOBT result requires further
investigation, including clinical examination for benign
causes of bleeding, and is likely to require referral for a
colonoscopy. There is no need to repeat the FOBT.
A negative result
A negative result does not guarantee that an adenoma or
cancer is absent, as the lesions may not be bleeding or the
bleeding may be intermittent. The FOBT does not need to
be repeated, but the patient should be instructed to report
any persistent change in bowel symptoms.
All patients, regardless of FOBT results, should be
encouraged to make healthy lifestyle choices including;
avoiding excessive consumption of red and processed
meats, high-fat dairy products and highly refined grains,
starches and sugars, maintaining a healthy body weight,
undertaking regular exercise, not smoking and drinking
less than two standard units of alcohol per day.
References
1. Hewitson P, Glasziou P, Irwig L, et al. Screening for colorectal
cancer using the faecal occult blood test, Hemoccult.
Cochrane Database Syst Rev 2007;(1):CD001216.
2. New Zealand Guidelines Group (NZGG). Guidance on
surveillance for people at increased risk of colorectal cancer.
Wellington: NZGG; 2012. Available from: www.nzgg.org.nz
(Accessed Jun, 2012).
COMING SOON
Appropriate use of
FOBT for colorectal
cancer detection
Download this audit soon from our website:
www.bpac.org.nz
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